Type 2 Diabetes Remission in the GLP-1 Era | Prof Roy Taylor

0:03Just under three years ago now, you came on and we focused on that episode on this question of, can you reverse type 2 diabetes or can you put it into remission? Three years on, have your thoughts on that question, have they evolved or changed in any material way? Well, I'm very pleased to say that the central matter of the potential reversibility of type 2 diabetes is absolutely solid. Now, that's quite important because it was such a revolutionary change when I was able to announce that in 2011. And since then, we've really put the building block steadily in place. And so it's been a matter of steady progress.

0:49It's taken a long time to be assimilated, but there are national programs now that use my methods to achieve not only reversal of type 2 diabetes, but durable remission of type 2 diabetes. So that's really quite exciting to see this all develop. And there are some other aspects that are on the horizon, especially in respect to pregnancy. So yes, we're in a good position with moving everything forwards. Let's start with your model. Can you give us the two-minute version of the twin cycle hypothesis, or perhaps more accurately, model, I should say, how a small sort of chronic calorie excess, as you explained to me last time, ends up causing this dysfunction in the liver and pancreas and to a point where someone is diagnosed with type 2 diabetes.

1:45Yes. If you wind back to 2008, we had assembled all the basic building blocks to understand that fat in the liver was bad news in type 2 diabetes and that it was potentially able to be taken out of the liver by weight loss. And we knew some things about the way the insulin-producing cells worked that could potentially tie it together. Now, when the final building block dropped into place, it took me quite a while to figure out how all these things would be interrelated. But eventually, the twin-cital emerged. And this was the idea that there was a citle, a vicious cycle in the liver, which started going, and that knocked onto a vicious citle in the pancreas.

2:40And as they ground slowly on together, they would interact, the effect would be magnified, the end result was type 2 diabetes. Now, I found that this was important because it was testable. Now any hypothesis is interesting, but it's only going to survive if it's tested to the full. We try and defeat the hypothesis to try and overturn it. And so this hypothesis could easily be overturned by getting people with ordinary type 2 diabetes to lose weight. And if all my predictions about what would happen in the liver, in the blood, and in the pancreas didn't happen and the diabetes didn't go away, the hypothesis was wrong.

3:28But it turned out the hypothesis was crashingly correct. And that's what we published in 2011. That was demonstrating just what causes type 2 diabetes. And it's really quite exciting to see the way that the mechanics of this disease works. Everything else flows from that. But of course, as soon as this was announced, people were saying, could I get rid of my diabetes? And so I had to turn my attention to possibly turning this into a tool that could be used in clinical practice. And over several trials, we did that. It works very well. It's a challenge to anyone, but people who are motivated find it the easiest way to lose weight.

4:17And I should say, we're talking about losing quite a lot of weight, 15 kilograms or about two and a half stone. That is possible. And we're able to say with confidence, this is the best way of dealing with early type two diabetes. And now we have our national program that puts this into practice in England. Can you remind us, what are the conditions that predispose someone to storing fat in the incorrect place, to storing fat within the liver, which kind of kickstarts that twin cycle model that you speak to in the first place? The critical factor is the matter of eating. Eating and burning energy, of course.

5:06If people are taking in just a few more calories every day, then they're actually burning in, running their body, having their heart beat, having their lungs expanding their tract, all that energy, as well as moving around, then those few extra calories are going to build up. and anyone's body can only deal one thing with it and that's to turn it into fat and it gets stored. Now that's the absolute starting point but then the luck of the draw kicks in because we know that some people can store a vast amount of fat and never get type 2 diabetes. You might say they're quite lucky. But people have only a finite capacity for storing fat under the skin.

5:58Some people, like me, don't have very much capacity at all. And for those people, if they put on even a modest amount of weight, they can get the fat building up in the liver and start off this horrible process. So here we have a combination of the genetic predisposition, but the absolute switch on or switch off, which is the amount of fat that's being stored in the body. Is that inherited predisposition to storing more fat ectopically? So when I say ectopically, I don't just mean centrally, I mean inside organs to be distinct there. So within the liver. Is that related to, I know on your model and previously we've spoken about muscle insulin resistance, and it seems like you need the chronic energy excess plus some insulin resistance in the tissue to create the conditions where someone begins storing excess liver fat.

7:04And I know, I remember Ralph DeFranza's Banting lecture. And within that, he stated that people who are destined to develop type 2 diabetes inherit a set of genes from their parents that kind of renders these tissues insulin resistance. Is what he's talking about, is that the muscle insulin resistance piece in your model? To a large extent, yes. But there are other more important parts. The first is the genetic capacity for subcutaneous fat storage. Now, we know that there are 50-odd genes that actually determine this in humans. So that is genetically determined. You have the luck of the draw, the genes you inherited from your parents.

7:51And if you're able to store a lot of fat subcutaneously, then you may escape any ectopic fat. But if you have both a bit too much fat and a limited capacity, then it will build up. Now, Rolf D 'Afranzo pointed out that insulin resistance in muscle was an early feature in type 2 diabetes. And that's absolutely correct. And it does contribute because if after a meal the body can't store enough carbohydrate in muscle as glycogen, which is a store that forms in muscle, after every meal you and I will store about 30 % of our meal carbohydrates in our muscle. But people who are relatively resistant to insulin store much less.

8:42But after each meal, anything that isn't stored has to be stored as fat, and the organ that makes the carbohydrate into fat is the liver. So there we have the link between those early studies of Ruben Andrews and all the greats. Walter Fronzo brought all that together and put it into a model, which is broadly in agreement, but it didn't extend to explaining anything like reversibility. That wasn't dreamt of in the time. So yes, we have muscle insulin resistance. That's largely genetic, but it can be exacerbated by accumulation of fat. So we have a vicious cycle, if you like, in muscle, but that's not a big deal in the wide escape of metabolism.

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11:13I was reviewing that work and trying to make sense of it and then thinking about your work. And the question I have is, is the liver upstream of all of that? If you get the liver fat down, do all of those things just tend to normalize? One thing that Ralph didn't do was to put any dimensions on the importance of each bit of it. The liver is wildly important. The muscle is certainly a major player as well. The beta cell is the part that gets finally knocked to bring about diabetes. But really, all the other bits of either no importance or trivially important. So, for instance, a brain. Yes, there's some research that shows, yes, you can produce this effect or that effect, but it's a tiny, tiny, tiny effect.

12:05So Rolf's ominous octet was over-complicated and it didn't help move us forwards because he was putting everything in a big pile on the table and there was no sense of proportion. Whereas pulling it apart with a physiological approach, we were able to see what really matters and were left with a much, much simpler model of the liver coiling the shots, muscle being relevant and the beta cell eventually turning up its toes. Is type 2 diabetes just a blood glucose control problem? I know that the ADA says remission is if you normalize HbA1c and you're not on medications, but with your understanding of the complexity of the pathophysiology, if you get liver fat down and you normalize HbA1c, Have you addressed all of what type 2 diabetes entails?

13:03Yes, and that announcement by the American Diabetes Association, which was incidentally an association with the European Association and Diabetes UK, so it was a joint consensus, it pointed out that after weight loss, and that's a critical thing, if it was possible to stop all tablets and bring the HbA1c into the non-diabetic range, then all the other abnormalities would have corrected. And the major abnormality that has corrected is the liver fat with the knock-on into the amount of fat produced in the blood. So the announcement that you could use just HbA1c to see if you're in remission is a simplification which was important.

13:55It rolls everything together but it packages up the critical matters that change and so what's changed at the heart of it all is fat metabolism and that's the driver for type 2 diabetes and that knocks on to allow the Hb1c, the blood glucose control, to normalize. As long as you lose enough weight to get below your personal fat threshold, which is going to be inherited or genetically determined to some extent. I saw that you recently were also interested in liver function tests. And I found that paper very interesting where you were able to show that for people that had elevated liver enzymes at baseline, that as they lost weight, a reduction in those liver enzymes associated quite strongly with a reduction in liver fat.

14:54What's the clinical utility of that beyond just measuring someone's HbA1c? Because I imagine HbA1c also would track with liver fat. First of all, it has to be said to set the context. liver specialists know that using the ordinary blood tests for the liver is not a good way to diagnose fatty liver so it's not reliable and if asked is it worthwhile measuring the liver function tests an expert in the liver would say well no but we did something rather different We measured sequentially during major weight loss. Now, what we can say is if the liver function tests were on the higher side, not necessarily abnormal, but higher at the time of diagnosis of diabetes, and then the person lost weight, if the liver function tests normalized, the liver fat would have gone away and that would have been job done from that point of view.

15:57Now, the importance of this, if we just go back to the doctor sitting in his office or his clinic, the patient in front of him wants to know, but how can we certain that my fatty liver's gone away, doctor? Well, we can actually be absolutely certain for those people who started off liver function tests. We have to be quite upfront and say they're not raised in everybody, in which case that's not a useful guidance. But it's raised in so many people that this is a very useful clinical pointer. So in the office, the doctor can look his patient in the eye and say, your liver fat will have normalized.

16:37And that was an ALT over 40 and a GGT over 35 or something like that? Yes, that's correct. How long does it take typically, on average, Roy, when someone's losing weight based on direct and the other trials? How long does it take for someone to start seeing a reduction in liver fat, normalization of HbA1c and liver enzymes? And the answer is very rapidly. If people go on to the Newcastle diet, the 800 kilocalories per day diet of soups and shakes, which sounds very formidable, but in fact people like it once they're on it. If they go on to that, then within seven days their liver fat will have fallen about 30%.

17:30And rather more than that, the bit of fat in the liver that is actually doing the damage, though it's not the triglyceride that's actually causing the damage, it's a knock-on effect of agents like diglycerides, we can't measure them directly, but we know that they will disappear faster. And we also can turn around and say, yes, just look at that rapid fall in liver fat of 30%, the liver function as regards insulin sensitivity is completely normal at seven days. Now that is staggering, that we can normalise the sensitivity of the liver. I was shocked when we saw the data, because no one had expected this.

18:17And we have to be quite clear that the liver insulin sensitivity is a different matter from the muscle. Muscle insulin sensitivity hardly changes. So we've got a very fast change. And to complete the question, yes, we reduce the fat by a third at one week. And it's essentially normal by around about four weeks, four to eight weeks. So it's a very fast process. And interesting that we can see such dramatic changes. That point there that you just said muscle insulin resistance barely changes, is the significance of that, and I'm connecting dots here, it's the liver insulin resistance that's resulting in the increased fat in the liver or the other way around, which is causally connected, responsible for beta cell function versus the muscle insulin resistance.

19:11Is that the point you're making? That's absolutely the point. And for a long time, muscle insulin resistance was the focus of attention. But in a famous series of experiments of removing the ability of insulin to act on muscle, and that could be done by taking away the receptors in muscle in genetically modified mice, we found, or rather, not we, the researchers in the States, discovered that there was absolutely no effect on handling glucose. And they were shocked, because they thought that taking away the receptors that diabetes would happen, and it didn't. So you can be very insulin resistant in muscle and no effect.

19:56But as soon as you start running into fat problems, the story is quite different. So yes, the insulin resistance in muscle is permissive, and there's one other really important point that arises from your question, Simon, And that is, no, people remain relatively insulin resistant in muscle after getting rid of the diabetes. What does that mean? It means that that sort of Damocles is still hanging over them. In other words, if their weight goes back up again, there is 100 % chance that they will redevelop type 2 diabetes. because the basic genetic setup has not changed. We've merely changed what we're physically able to do as doctors, change the environment and bring about health in that way.

20:48That's testable as well, I would imagine, in that you could take someone who has type 2 diabetes, lots of liver fat, and give them a drug that increases insulin sensitivity just in muscle. Has that been done? Not exactly. when one group of drugs which appeared to increase insulin sensitivity in muscle was introduced, it caused great excitement. But it's now very clear that these agents acted by changing fat metabolism. So they weren't actually changing this mega dial in muscle, but they were affecting other bits around the edge. And those drugs, the TZDs, are no longer mainly in clinical practice because there were other much more useful tablets that were better than diabetes.

21:37Remind us what happens to beta cells in type 2 diabetes. Are the cells themselves undergoing apoptosis? Are they dying? Are they just dysfunctional and asleep? What do we understand from your research? And perhaps in that explanation, I appreciate this is a double question, but I think it's important. What's the relationship between what's happening in the liver and what happens in the beta cells. Connect that story for us. So first of all, starting from the beta cell, and if I cut to the chase and state what's going on, it might help things. So the beta cell has been suppressed by constant provision of too much fat, and it's gone into a state where it can no longer respond to a high glucose.

22:26It just can't connect the dots and put out insulin in response. So the beta cell is suppressed. And no, it's not apoptosed, and it's not dead. Those are both ideas that have been floated around for a while. And for a long time, the slow, steady decline of beta cell function that we can observe over 15, 20 years of type 2 diabetes was thought to be the beta cells dying off. But when we look at post-mortem pancreas? No, they're still there. And we now know that apoptosis is not relevant. It can be demonstrated, it can be found in animal models, but bear in mind those animal models are dealing with a very short span of producing diabetes.

23:17That's not actually anything like we see in humans. So that's the beta cell, and if we wind back to the liver, what's going on? Well, when there is excess fat in the liver, the liver starts producing more fat than it should. Now, one of the central jobs of the liver is to make fat for the body. It's a vital energy substrate that the liver supplies at the right about for the rest of the body. And the body can use it for energy. for instance, most of our energy overnight is produced by fat that's been put out from the liver, as well as glucose from the liver. But if we just come back to that fat, excess liver fat stored there will force the liver to put out too much into the blood.

24:09And so the poor old beta cell, the insulin secreting cell sitting there, instead of getting this much fat, is suddenly bathed in this much fat. And to put a figure on it, it's about a 50 % increase. It's not a trivial increase, the sort of change you might find in an epidemiological study of getting excited about a few percent. No, this is a major change. And in people who have susceptible beta cells, and again, that's a genetic phenomenon, this excess fat provision over a long period of time will cause the beta cell to effectively stop responding to glucose so well. So that's a story. And that's why the liver and the pancreas tie up as one of the central points of the twin-cital hypothesis.

25:03So you come back down below your personal fat threshold, you're getting fat out of the liver and pancreas, and you're sort of resensitizing these beta cells to glucose. They're better able to detect blood glucose levels and produce insulin? That's absolutely correct. And why in your trials, correct me if I'm wrong, I'm kind of racking my brain to think back to our previous conversation, I believe that people who had type 2 diabetes for longer were less likely to get into remission. What does that tell you about the beta cell dysfunction the longer you have the disease? The longer duration this beta cell is assailed by this excess of fat, the more likely it is to be moved to a position where it just can't reassemble all the apparatus needed to make insulin.

25:58Now, the rate at which that happens is strikingly different between individuals. On average, people in the first six years will be able to reverse their diabetes fine, about 90 % of them, but after 10 years, it's down to about 50%. After 20 years, it's a very small percentage. But I've seen two people who've had type 2 diabetes for 23 years and have both come off two lots of tablets for their diabetes. have remained clear of the diabetes merely by relieving the beta cell of its stress. And that tells me something really interesting about the beta cell, because we can predict that, yes, there is this genetic effect of being susceptible to fat, but there's also a different genetic access of, shall we say, durability, or able to withstand this attack.

26:55So those two people who are able to get rid of the fat and have the beta cells wake up, they were extremely able to just maintain the apparatus in cold storage, as it were, to bring it out when ready. Most people will have failed to do that at some way along the line. So you see, it is the fat that's causing the damage. And yes, ultimately, the beta cell can be irreparably damaged. But we know that there is a window of opportunity that can be quite large. Yeah, I have to imagine that is going to be part of future type 2 diabetes management, or hopefully, because I imagine that those subjects who go through weight loss and don't get their return in beta cell function, that's a disheartening experience.

27:45It is disheartening, but the people tell us that they're pleased that they did it. They're pleased that they did it because they feel so much better, and they will have been told that their index for heart attack risk has gone down considerably. Because even though they don't get rid of their diabetes, they do get rid of their liver fat, and the fats in the blood come good, as it were. So they're in a far better position. And I would add that we've had independent teams of psychologists investigate this because it is a question that comes up and it's an important question. And we find that there's no major disbenefit to people, even if the diabetes isn't reversed as such, there's still health benefits and people feel they've benefited by the experience.

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31:42And you've walked us through how that becomes impaired in type 2 diabetes. You've walked us through how that we can essentially, through weight loss, for many people, sort of wake up these sleepy beta cells and they're not lost and dead forever. Recently, I've come to learn, I had a guest on a few weeks back, Dr. Nicola Guess, and she was talking about the fact that beta cells also sense amino acids. and that there is some research, at least in people with prediabetes, looking at can you generate an insulin response through the consumption of protein without weight loss? What's your kind of view on that and take on that area of the literature?

32:27This is an interesting area of literature and it is one that could potentially deliver some advantages, but the amount of protein that's needed to generate this response is really very considerable. So early tests on looking at whether this would work in type 2 diabetes just don't work. It's not possible to get enough protein to the beta cell fast enough. But let me tell you about the test we use to see whether the beta cell is working fully has woken up. What we do is put glucose into a vein at a set rate to suddenly raise the plasma glucose. Very small amount, just 3 millimole per litre, which is really well within what we'd see in a normal person after a meal.

33:21And that causes the insulin producing cell to produce a spike of insulin. And that's what we test as the most important thing. But then we raise the glucose further and we give a bolus of the components of protein, one of the building blocks of protein called arginine, but we have to give 5 grams of this as a bolus, whoosh, into a vein all at once. And the beta cell then responds maximally and we get a massive output of insulin from the beta cell. So yes, we can stimulate the beta cell using protein, but it's jolly difficult to get enough in at any one time to be able to have a meaningful effect upon glucose control.

34:13So whether this line of research could be developed in some clever ways that have not yet been thought about, that's an entirely plausible option. So worthy of attention, but so far, a long way from clinical usage. I think the context that Nicola was describing was, for some people, weight loss may not be indicated or safe. And I think she referred to certain elderly, for example. I know you've done the retune study, so you may have a different opinion in on that or perhaps earlier in the disease process say for example pre-diabetes is manipulation of the amount of protein in the diet and even the types of fat like saturated fats versus unsaturated fats do these things really make a difference when it comes to blood glucose control or are you of the view like to really shift the needle but the the weight loss is needed to get at the very basis, the cause of type 2 diabetes.

35:16The weight loss is needed because the beta cell is such a beautiful instrument, able to produce insulin so rapidly after a meal. And mimicking that normal rapid response, followed by a sustained insulin secretion, is, I think, almost impossible to imagine being achieved by manipulating protein. improving glucose control. Well, that's a possibility. Studies so far following this up have not been successful. They've not shown it. But there's always the opportunity for new approaches, fresh thinking. Nicola is a very astute scientist, dietician. And so I'll have to watch this space with regard to what Nicola's got in mind.

36:04But the story so far is interesting theory, but so far, nothing practical. Last question on that, on liver fat in particular, are you familiar with any of the research looking at the types of fat that someone's consuming? Say it's saturated fat or monounsaturated or polyunsaturated fat and independent of calories. So we've established if you're eating in excess calories and you're above your personal fat threshold, you're going to be storing fat in the liver to some extent. What about independent of calories, if you're eating more or less saturated fat, more or less polyunsaturated fats, does this affect the amount of liver fat that you end up with?

36:48No, it doesn't affect the total amount. It may affect the degree of saturation of the fat in the liver. Now, most of our fat is around 50%, call it saturated fat, 50 % mixture of monounsaturated and polyunsaturated. And if we look at what we're consuming, that's food as well. So butter, which is labelled in everyone's mind as being saturated fat, is almost 50 % monounsaturated fat, that wonderful stuff that we try and get from our Mediterranean diet. Well, eat butter. Well, it's not quite as simple as that. Does it make a difference? Well, we know that cells in the laboratory given saturated fat will respond to insulin less well than those given unsaturated fat.

37:41So there is, if you like, a scientific question to be asked there. But the various dietary studies have been relatively unimpressive in showing a difference between modifying the degree of saturated fat and unsaturated fat. In practice, it's very difficult to separate the saturation question from the total amount, because saturated fat tends to be more prominent in all the goodies. The nice tasty meat in fat, the nice tasty cheese, etc. Whereas unsaturated fat, possibly less attractive, margarines, oils of various kinds. So it's a difficult question and it's one that I'm still grappling with. There's also a lot of different types of saturated fats and polyunsaturated fats because those are umbrella terms.

38:35So this question gets even more complex when you start drilling down to that level. It does, but basically we all eat real food. And so we're limited to certain mixes that are present in those foodstuffs. So what about if we think about it more at a macro level then and less zoomed in on the particular type of fat? Is there a dietary pattern that you think is best for maintaining healthy levels of liver fat? And I guess by extension of that, I'm really saying what dietary pattern do you think is best for maintaining a healthy body weight below your personal fat threshold? If I was to be answering that in a joking fashion, I would say it's clearly the traditional Japanese way of eating.

39:22We've got to broaden the focus here. We've got to consider that our views of eating in Western Europe are very different from much of the rest of the world. Ethnicities vary in what they eat. And so the question has got to be approached from this very broad point of view. I would answer it by saying no, there is no one diet that I would recommend for everybody because individual preferences vary and the way in which people can keep a reasonable limit on the total amount of food that they eat is going to vary. And at the very simplest level, some people find it virtually impossible to follow a low carbohydrate diet.

40:09Some people find it virtually impossible to follow a low fat diet. And so we've got the personal preference bit. And this is one of the factors that's been completely overlooked in the nutrition field, to my knowledge. And it needs to be brought to the fore, because advising someone how to eat really is going to depend critically on how they eat in order to keep the total calorie content down. We've got to avoid this terrible tendency for body weight to rise in Western Europe. It's an average of half a kilogram a year from the ages of 20 to 60. That is awful. It results in a lot of accumulation of fat.

40:58So from the point of view of health, that's the big question. What pattern of eating is going to allow you to keep your calorie intake balanced with your calorie expenditure. Something that the individual enjoys can sustain and keeps them fuller on less calories. If we were to kind of survey people and say, what is the root cause of the excess energy consumption? I think people would point to a variety of factors, but one of the main ones being the food environment. And then people would say, this is exactly why GLP-1 medications are proving success because they're treating food noise within an environment that is leaving people very susceptible to the overconsumption of calories.

41:49Yeah. Just going back to your point about the ultra-processed food, I was really dancing around that before. Yes, if people are eating ultra-processed food for the major part of their food intake, and unfortunately in the UK, 55 % of food intake falls into this category, those people are going to be beset with the very design features that have been built into the food. Because these are purpose-designed foods to fuel appetite, to cause people to eat more, and sell more, and to not feel hungry after the meal. So they'll eat more again. Now, faced with that carefully designed onslaught, the human body can't really cope.

42:35And so in the individual assessment of diet, yes, that junk food question, the ultra-processed food question, comes up to a large extent. From the population perspective, it's a bit different. And legislators have just got to be persuaded that they must move on this particular poison because it is a metabolic poison and we expect legislators to act on lead poison, on carbon monoxide, on whatever. And so here we've got a population issue which I haven't really touched on with regard to the junk food. Let's change gears a little bit here and go through the most recent direct trial results. So in our last conversation, you shared with us, I believe, the two-year data.

43:26And since then, there is now five-year data that has been published. So if someone's not familiar with the direct trial, what's the synopsis of this? What type of study was it? What was the dietary intervention? And then perhaps we can get into how the results have kind of changed from year two to year five. The direct trial was designed to test whether we could actually have a clinically useful weight loss program run by family doctors, run in primary care, that would build upon what we already knew. We knew type 2 diabetes was reversible by major weight loss, and we also knew from a second study that it would stay away provided weight loss was maintained, and we knew it affected short-term diabetes.

44:14So we designed a randomized study, which meant that people at random were allocated either to healthy eating, just the best guidance of the time, or to rapid weight loss, followed by advice as to how to keep the weight down. and we showed indeed in the first year that with the weight loss diet almost 50 % of people were in remission 46 % striking finding and the weight loss at one year was 10 kilograms and two years it was about 8.6 kilograms and the proportion of remissions had fallen but what happened after that And we now have five-year data, which is really very exciting to see what's happened to these people who are managed in these two different ways.

45:08So to press ahead, what did we find? Well, first of all, in the intervention group that had the advice about rapid weight loss and trying to keep it off, all the wise advice beforehand, the nutritionists and the dieticians said, rapid weight loss is followed by rapid weight gain and people are going to overshoot. Now, that's one of these beliefs in the nutrition field, which has absolutely no evidence. It's an idea that's been put around, and because people tell it to each other, it becomes believed. And so the belief was very much against the direct trial. People thought that this was a terrible thing to be doing.

45:49But in fact, we were able to show at five years, people were still substantially below their baseline weight. At five years, there were an average of 6.3 kilograms, that's over a stone, below baseline. Now, that conveys all sorts of health benefits, but there was sufficient weight regain for the proportion of remissions to go down, and the total proportion of remissions was down to about 13 % at that time. But of course, it was the people who'd kept the weight off that stayed free of diabetes. Because yes, diabetes will stay in remission, but we have this very human problem. In interpreting those data, I would point out that the direct follow-up study was designed as an observation.

46:40This was not an expensive research study with teams of dietitians, exercise advisors, other people, reviewing people every week. These were people just left to get on with life in their own devices, seen every few months by the practice nurse, no one else. And so the fact that this very low-cost intervention could achieve this huge amount of weight loss at five years is of great interest. And it opens up the critical question, okay, what can we do to help people keep the weight off rather more effectively? And that's the$64 ,000 question. What we saw was that it was a fairly rapid weight regain at first, but from about three years onwards, people plateaued.

47:33They were not heading back to baseline. They were going along. They were able to control their food intake better than before. But we can improve on this, and so this is a big topic of research for the future. A direct five-year, I think, has been well-received, and people accept its wide findings, not least because of one critical thing. Now, what do people with diabetes want? Well, they want their health. And what's against health? Well, any time you need to be admitted to hospital is a disaster. the number of admissions to hospital in the weight loss group was exactly half that in the ordinary group.

48:18So this is a profound effect on health. And even more than that, the number of cancers in the weight loss group was substantially reduced compared with the intervention group. It is never mentioned that one of the biggest factors underlying the common cancers, not all cancers, but the common cancers, is increased weight. Well, in direct five-year, we demonstrated if you take away that excess weight, boy, the number of cancers goes down. And that really turns heads and makes it worth substantial consideration. How can we do this, but even do it better? Yeah, I didn't realize you guys were looking at those hard outcomes.

49:04So you were actually looking at differences in cancer, presumably other complications of diabetes like cardiovascular disease or retinopathy. Yes, retinopathy we didn't investigate because in the group of people we were looking at, type 2, the first six years after the diagnosis, retinopathy is just not a big issue. We need to keep an eye on it, but it's not a big issue. The number of people involved in diet was too low to show a difference in cardiac outcomes. And so no, we weren't able to show that. But we were able to demonstrate that the risk calculator, we can calculate the 10-year risk of heart disease quite effectively.

49:46And that had dropped to normal in the people who were in remission. So we're pretty convinced that it will affect heart disease in the long term. And we even call on data from another very large study that's been running in the States for a long time, the Leukahead study, which produced quite useful weight loss. And some 12 years of follow-up, there was a major difference in the number of heart attacks and strokes, etc. And that depended how long people have been able to maintain the remission of the diabetes. This is not what the Leukahead study was designed for, because of course remission of type 2 wasn't even thought of at the time when the study was started.

50:35But it's very valuable because the doctors could look back at the data they collected and see, ha, these people were actually in remission for four years. Wow! The heart disease rate dropped by 60 odd percent. It was about a third of what it was otherwise. eyes. So you can see that the effect of this weight loss producing remission is highly likely to produce a major benefit for the heart. That's a big point I was making. Owning a home is wonderful, right up until it isn't. One minute you're having a coffee, the next you're ankle deep in water from a burst pipe that is chosen, as they always do, a Saturday.

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53:15Right now, Skylight is offering our listeners$30 off their 15-inch calendars by going to myskylight.com forward slash the proof for$30 off your 15-inch calendar. That is myskylicht.com forward slash the proof. No excuses. Get organized with Skylight. you mentioned earlier that the the durability of remission seems important to learn more about now what is it that makes those that sustained remission at five years different to those who were in remission early on in the study but no longer in remission at the end of the study i know it might be preliminary but are there any characteristics behaviors or or other things that make those in remission at five years distinct to the others in the study?

54:10In general, there were a few pointers to that, but there was a tendency both in the five-year follow-up of direct and in the NHS England population study to see that older people actually managed rather better to keep their weight down. Now, this is hugely understandable. Younger people are busy, they're busy with family, busy with jobs, busy with all sorts of things, activities. They lead a hectic life, and thinking about the weight and the complications of the future is not high on their mind. Older people have got more time, by and large, and sometimes are really much more interested in their health because their friends are suffering.

54:55And so there is an effective age. We wish it would be the other way round, but it's not. And unfortunately, there's also an effect of economic circumstances. So we looked at the socioeconomic categorization of where people lived, and we found that in the most deprived areas, initially, people did just as well. They can lose weight just as well as people in the posh areas. But over time, it was very clear that their living circumstances, the stresses of life, etc., were such that they were less able to maintain remission. And so in the NHS England population study, I think we had something like 31 % of people in the affluent areas in remission at one year, but only something like 19 % in the least well-served areas.

55:52So I would highlight those two factors and also use the opportunity to say, hey, it's similar between men and women. You mentioned that this five-year study is really observation after the initial trial from, I think, from two years. So describe the intervention a little bit more to us because I'm not sure everyone's clear on that. And was that, I believe it was like a 12-week low-calorie diet. Was that something that people did once and lost a lot of weight? Did they do it multiple times in the first few years? Were they continuing to do that between years two and year five? What did that look like?

56:29The direct study intervention was set up by providing training for the practice nervous in each practice involved. So in a way it was a study of the training effect. The nurse had eight hours of structured training in how to deliver the weight loss and then how best to try and help sustain it. The weight loss, as you say, was achieved by using low-calorie soups and shakes, so liquid meal replacements, along with advice to take no alcohol, because alcohol is so calorific. And over 12 weeks in this big population-based study in general practice, people achieved weight loss of around 15 kilograms immediately at the end of the diet.

57:18They had to slip back to 10 kilograms at one year. Did they repeat it? Well, not unless they needed to. And so we had devised an advance rescue packages. Because, hey, life's never straightforward. Stresses happen. The roof starts leaking. There's family illness. There's financial problems. Something else takes over your mind. You can't focus on keeping your weight down all the time, necessarily, in the face of the slings and arrows of everyday life. And I was actually rather horrified how often this happens in this general practice population. So we had these pre-planned rescue packages. If people put on more than four kilograms then they would be offered a full soup and shakes program again for usually a shorter period of time.

58:11If they put on more than two kilograms they were just given advice about what to do, maybe they could use one soup or shake instead of their dinner, that sort of approach. And these were used intermittently and around 50 % of people required those helping hands, usually once, sometimes twice during the course of the two years. So we did look after people in that intensive way during the two-year period, and at the end of the two years, the weight loss of about 8.8 kilograms was really very reasonable. And at that time, we had some 36 % of people in remission. So that's the intensive part of the study, which as you say, then turned the corner and it was observational.

59:06Is there a way to compare the results, particularly at five years? So once people go out into the real world and it's just a free living population which in some ways is is more generalizable is there a way to compare the outcomes to the results looking at weight loss medications and changes to blood glucose control or type 2 diabetes appreciating that technically from a definition point of view being on a weight loss medication and achieving normal hba1c is not quote-unquote remission because you're still on a drug, but in terms of their effect on the underlying disease and blood glucose control, how do you compare these interventions?

59:52Yes. The scene has changed with the development of these very potent weight loss drugs. These are amazing drugs. We always try and develop these so-called silver bullets that precisely hit their target. And for decades, even centuries, people have been trying to devise a way of tuning down appetite. We know where the appetite centres are in the brain, but designing a drug to affect them particularly has always been elusive until just recently. And so, boy, this is a major triumph of pharmacology. However, we're at a very early stage of learning how to use them. What we know so far is, yes, the most potent agents will produce about 10 kilograms of weight loss when used in real life.

1:00:42Now, I say that as a start deliberately because the companies that make these drugs design studies to market them, and that's where the 20 % comes from. But that is achieved using a very intensive lifestyle program along with the drug. Now, that's not feasible for most doctors to deliver from their office, from their clinic, and so several papers have now been published showing that the rate of weight loss of these agents is about half that published in the initial pharmaceutical studies. Nonetheless, 10 kilograms of weight loss is not to be sneezed at. That's phenomenal. But when the drug stopped, the rate of weight gain is such that it's gone back to baseline within 18 months.

1:01:36Now that is, you'll appreciate, much more rapidly than during the direct study, whereby we're able to sustain weight loss over two years, and even without any complicated follow-up, up to five years. So there is a problem with the weight gain. There's a problem with the cost of the agents, and of course there's a problem with side effects. The side effects are troublesome, and in the real-life studies, at least half of the group will stop taking these agents because of side effects. Bad nausea, vomiting. Usually, that's just for a short period of time when they're started. But whatever. This is just reporting on what happens in the studies.

1:02:23And then there are more serious side effects, which are actually very rare to date. So they do look fairly safe, but there is a rare but distinct incidence of inflammation of the pancreas. And that is very bad news. It's a serious illness, taking you to intensive care for a period of 12 days or so on average. and their belonged hospital stay, it's not nice. And if these drugs are used in large numbers in the population, this very rare side effect will be seen quite often. So there are concerns about the widespread use of these. As I say, their place is still to be sorted out. And the specific question that you asked me is as yet without an answer.

1:03:16How does it compare directly? And we can't compare directly as yet. We can say, well, one study showed maintained weight loss of six kilograms at five years and use of the drugs, everything had gone back to baseline within 18 months. Well, yes, but there were probably different populations of people and I'd be uncomfortable making a direct comparison. It gives us an approximate idea. But the study needs to be done to compare these two modalities. Because I know many of my patients would far prefer to take a non-drug approach to dealing with this environmental disease, this disease that's caused by excess food.

1:04:03Well, can we not deal with it more simply? Don't you think it's a good thing, though, to have more options for people to get below the personal fat threshold? I'm completely on board there. Yeah, this is a great thing. The caveats I've outlined will become clearer with time. We're more certain about this. The health advantages for people who either can't or don't want to adopt a dietary approach to doing this are very considerable. Potentially, they may need to continue taking the agent. Because the big questions that form in my mind is, OK, can we use these agents to control weight and then at a very low dose, ongoing in some cost-effective manner, to keep the weight off?

1:04:47That's a one option. Or alternatively, as you alluded to before, could they be used in courses to get the weight down, and if the weight's regained, get it down again? We know that yo-yo dieting is not specifically bad. That's another rumour without any substance to it. So that's an option, perhaps a less desirable one. People would need to keep changing their clothes size, which would not be popular. So all of this is to unfold. And I would urge caution in any definitive position just at the moment, because we've got a really exciting group of drugs that do what they say on the tin. But learning how to use them is going to be quite a long job.

1:05:30When I look at this, and I think the points you raise are really fair and reasonable and balanced. Also, I think that you can apply a similar level of thinking or line of thinking to what you said about the GLP ones in real life. Clinicians not necessarily getting the same results in the study, I have to imagine, would be similar with very low calorie diets. If you don't have a dietician working with you, you don't have the community program infrastructure, for example. I wonder if for some people, the best of both worlds is to be combining intervals of certain calorie restriction kind of programs like what you've been studying, also with pharmacotherapy that helps them from an appetite and perhaps adherence point of view.

1:06:16And in doing so, maybe the five-year results look even more promising in terms of remission. This is entirely possible, especially with the advent of a tablet form of these drugs. As you know, previously they needed to be injected, but the advent of a tablet form makes that all the more possible. And yes, we could be looking at a very different future for type 2 diabetes, although I have to hark back to my point about health service economics and a sensible approach to this nationally. There has to be some combined approach of trying to deal with the food supply issue, as well as use of these agents.

1:07:04We're at an exciting time of learning how to use these, and I'd be the last person to stand in the way of their use. Bear in mind, my research was driven by the question, what causes type 2 diabetes? How can we understand the mechanisms? In a way, I've been hijacked into supervising studies of remission, etc. It isn't what I had intended to do, but clearly it's a huge practical benefit, major benefit to individuals. But we can use our pathophysiological knowledge to study these agents. Now unfortunately the drug companies are still pretending that they have a specific effect on diabetes, that they're acting as a natural incretin, and there is no evidence of that.

1:07:53Absolutely not. You can find that out by just looking at the legally approved literature for these drugs. Not a single mention. Whereas it's implied by word of mouth. I tattled one of the senior executives of one company about this. And he said, oh, we don't claim that. Well, it's not the impression that's given. So note, these drugs do an amazing job at removing fat from the body. I can predict absolutely they will reduce liver fat. I can predict they'll reduce the secretion of fat from the liver and they'll relieve the fat burden from the beta cell, which of course wakes up. But the idea that there's some magical incretin effect has always been something of a Cinderella.

1:08:40So do I have it wrong? I thought GLP-1s, at least what I read and heard from others, I thought they did increase insulin secretion from beta cells. Is that not true? In you and I, the very sharp spike of GLP-1s after a meal will help kickstart the insulin production. It's a modest boost. It will probably add on another 30 % to your peak insulin. That has not been shown to be reproduced exactly, but certainly you can detect an effect of giving GLP-1s to increase insulin secretion in some circumstances. However, in none of the drug company studies is it's shown that insulin levels actually rise in response to a meal, more so than they would have done otherwise.

1:09:31So this is the basis of pointing out, look, these are fantastic drugs with silver bullet targeting on the appetite centre, but don't confuse the issue with trying to conflict them with the natural action of the hormone, which has such a beautiful, sharp profile to do an incredibly specific job. You mentioned mechanism and you understand the pathophysiology more than just about anyone on this planet. And I've seen some people talking about these drugs, particularly retitrutide, which has that glucagon component, suggesting that the metabolic health benefits go beyond weight loss. And this is perhaps speculation, but I've heard people even describe that compound in particular as a kind of like a liver fat burner directly acting on the liver and causing or promoting hepatocytes to burn fat.

1:10:32Is that anything that you've come across or is that accurate that independent of weight loss, these drugs are influencing the model that you described at the outset of this episode? I can't give an answer to that with that very new drug, But I can point out that these commentators are probably referring to weight loss as conventionally used. Trying to get a kilogram or so off. No, that doesn't cut it. Let's cut back to what happens to liver fat with the weight loss. It goes back to low normal. You can't go lower than low normal. And in the retune study, for instance, it went down to an average of 1.8%.

1:11:13You know, drugs can't have a supernormal effect. And so I think the claim that they can do better than substantial weight loss is simply not true. So, for instance, we know liver fat goes back to normal. We know that the 10-year cardiovascular risk index goes back to normal. And so we're looking at complete normalization, provided we grasp that we're talking about 10 to 15 kilograms of weight loss. So that's the issue. I've been using WHOOP for over six years, and I can confidently say it keeps me on track when it comes to my sleep and exercise routines. The next generation of WHOOP isn't just tracking your workouts.

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1:12:49The last kind of class of drugs that I wanted to quickly ask you about, and it might be a similar situation where it's too early to know, but if I recall correctly in our last conversation, you mentioned to me that you kind of like to deliberately keep exercise out of the weight loss phase when someone's doing the low calorie dietary intervention. And that was to prevent sort of compensatory eating. When people finish exercise, it's very easy to go and eat a lot of calories. And yet we have spoken about the importance of muscle for blood glucose control and fat building up in muscle. And so what I wondered was there's this new class of drugs that I've seen people talking about called myostatin inhibitors.

1:13:35And when I say new, they've been around for a while, but there's some phase one and phase two trials that are looking at do these compounds sort of protect muscle during significant bouts of weight loss? And what I wondered was whether you think that is an interesting mechanism and something that could potentially be beneficial to pair with whether it's a GLP-1 or to pair with these very low calorie diets where people are losing a lot of weight quickly. This idea of protecting muscle is a very curious one. There's been almost a hysteria about fear of muscle loss during major weight loss, major dietary weight loss that is completely unbalanced.

1:14:19the genuine loss of muscle due to 15 kilograms weight loss is exactly what you would see if you were to put on a weighted vest 15 kilogram vest and walk around for eight weeks your muscle mass would have increased by a probably two percent that sort of small amount you would be stronger you take it off so you take off 15 kilograms and walk around And guess what happens over the next eight weeks? It goes down. There is a small, genuine change in muscle mass. But because people have been using bioimpedance to measure so-called lean body mass, they look at this big weight loss, big loss of non-fat loss, and say, that's terrible, all this muscle's gone.

1:15:10And it's not muscle, it's fluid in general. and because of this mix-up we have if you like an industry of trying to prevent muscle loss during weight loss and I would just point out that the very careful psychological studies that were done on our research volunteers showed that they reported increased physical activity, people in manual jobs reported no difficulty with that and reported an improvement in quality of life overall. So this idea that rapid dietary weight loss with adequate protein supplementation produces muscle loss is illusory. I've got to add to that. Use of the GLP-1s is different because people can choose what to eat in their own homes and I wouldn't be quite so sanguine about that because yes, people do need to keep up their protein intake during weight loss.

1:16:11Very easy to do with the packet meals, the soups and shakes, they're more than 25 % protein now. And so that's not an issue. But in general, there is no problem with loss of functional muscle during weight loss. There's been a conflation of that and what's called sarcopenic obesity, which is when someone is enormously heavy and they can't move around very much, of course, their muscle mass goes down. Now, that's a real condition. And of course, that deserves resistance exercise. We can deal with this. We know the mechanisms involved. But using drugs to prevent this illusion strikes me as being just a little odd.

1:16:55Yeah, I asked that question because I think the audience is going to come across some of these studies there was a study called embrace that came out recently that looked at trisepatide which is the dual agonist and they had a a group on trisepatide alone and trisepatide plus this myostatin inhibitor and those in the group on the myostatin inhibitor lost about 50 percent less lean mass. But to your point, not all of that lean mass, even in these GLP-1 studies, is muscle. Some of that's water, connective tissue, bone. So I've seen a number of people recently commentate or speak about the fact that even in the GLP-1 studies, the early kind of narrative around significant muscle loss was perhaps overstated.

1:17:47Yes, that's certainly the case. I mean, I'll certainly watch with interest the further development of the myostatins. I've only glanced at some of the earlier papers, and they didn't strike me as being too remarkable. But, you know, obviously, the field moves on, more potent agents come on. And the thing about science is you need to keep a completely open mind and move with the evidence. So yes, maybe in another three years, Simon, we'll be able to have a detailed conversation about this. Something else you've looked at since our last conversation is weight loss in the context of gestational diabetes.

1:18:26What's the difference between gestational diabetes and type 2 diabetes? And why was this something that you were interested with your team to look into? Well, the interest comes very clearly from my own personal experience because for most of my consultant life, one of my responsibilities has been to look after the medicine in pregnancy clinic. That dealt with everything in pregnancy, from blood pressure, fibro disease, whatever. But of course, a large slice of it was diabetes. And gestational diabetes is the form of diabetes that comes on during pregnancy, usually around about the middle of pregnancy, and goes away or appears to go away after pregnancy.

1:19:14But in fact, it's just an early warning that that person is susceptible to type 2 diabetes. An early study that we did showed that the mechanisms involved are generally the same, but we were able to follow that up with a large population study looking at trying to achieve dietary weight loss after the diagnosis of gestational diabetes. So bear in mind, when I've already gone through half their pregnancy, the women who successfully lost some weight in pregnancy had less need for insulin and their babies were smaller. and those are two of the most important outcome indicators even though we could have done better with that study for various technical reasons and now the hunt is on to really find the answer to the question what happens if women lose a substantial amount of weight either before or in early pregnancy, will this actually prevent gestational diabetes?

1:20:23I would be astounded if it did not. If I just give you a snippet from my clinic, when I first took on that clinic in 1985, I would see maybe one person per year who needed insulin because of gestational diabetes. Now there's had to be created a separate clinic because there are more women with gestational diabetes than there are with other kinds of established diabetes. So this is because the weight of the population has gone up. It's not rocket science. This is a nutritional condition and it's capable of being affected. So a friend was who asked me, what should I really do to be maximally healthy before pregnancy?

1:21:09Get down to your ideal body weight, would be my answer. But of course, I have no business to say that as anyone coming from a medical point of view, because we've yet to really close the loop and prove this in a definitive sense. But the early studies are really exciting. And if we can affect this, we'll make a profound difference to the experience of women in pregnancy with the matter of cesarean sections, with the matter of babies that are very large and cause damage to the pelvic floor, hardly ever discussed. But that damage sometimes causes lifetime problems. We're into a big league here, and the answer may be simple.

1:21:58So if you were to hypothesize, you would say that women who go on to develop gestational diabetes probably have more liver fat pre-pregnancy? Yes. Now, we do know that to be a fact because of women being studied in between pregnancies when they've had one baby with a gestational diabetic pregnancy. Well, they've been studied, and yes, they do have excess liver fat at that time. So the answer is already home and dry there. So given that people can tolerate different levels of total body fat. How does a woman know pre-pregnancy if she has too much liver fat or perhaps a level of liver fat that's going to place her at increased risk of gestational diabetes?

1:22:47Is there a test that someone can do to see if they're over their personal fat threshold? Is it just looking at standard metabolic markers? What are the types of things that would perhaps kind of say or suggest to a woman that maybe she's better off losing a little bit of weight before pregnancy? Well, the strong indicators would be family history of type 2 diabetes. That's a surefire one. The second thing would be if the woman was of Asian or Far Eastern ethnicity or African ethnicity, the chances are higher and that has to be taken more seriously. And finally, older women are more prone to this just because the risk of metabolic disease rises with life.

1:23:34So those three points I would make. But, hey, this goes beyond the metabolism and to the wider aspects of pregnancy. Really, women need to look out for themselves the hard information on the risk of various problems in pregnancy related to weight. And that tells a story. Is there data, and you may have mentioned this, but if a woman develops gestational diabetes, what happens to her lifetime risk of developing type 2 diabetes? That rockets up. She has about a 50 % chance of developing type 2 diabetes. It's not quite clear why it's not 100%, and we don't yet have the information, I believe, as to whether this is solely explained by women who don't gain weight and those who do gain weight.

1:24:21What I'm hearing from you, Roy, in this conversation and our previous one and reading your publications, while the science is never 100 % complete, we know enough today about the development, the pathophysiology of type 2 diabetes to really put this into remission and significantly reduce the number of people living globally with type 2 diabetes and then suffering all of the downstream complications from that. And really, this is an implementation problem. We've spoken about durability. So three years on from our last conversation, we have this emergence of this class of drugs. We also have your NHS program and the feedback and data that you've got from that with your own intervention.

1:25:07Are you more or less optimistic that we can squeeze type 2 diabetes out of society at a population level? I think I'm more optimistic, especially with the NHS data, which is for a low-cost intervention for a health service to deliver to a nation. So that's impressive. But the bit that I'm least optimistic about is persuading legislators to make reasonable changes to food regulation, which is such an obvious point. So I think we have a sticking point there. And so this will be a major problem for the foreseeable future, I'm afraid. I wonder if GLP-1s kind of inadvertently affect the food environment through a change in demand of foods.

1:25:59That's a really interesting point. And yes, various high street bakery chains in the UK have had to start producing downsized articles because people were asking for a smaller sausage roll. I can't take a pasty that size. And so in restaurants too, asking for a small portion has now become acceptable. And this is a really interesting effect because, of course, one can ask for a small portion perfectly reasonably without being on a JLP1 agonist. So yes, it has actually engineered a change in society. Well, thank you, Dr. Taylor. As always, this has been incredibly informative. I've really love this episode.

1:26:42I enjoy geeking out on all the mechanistic stuff and also hearing about the real world outcomes. We all really appreciate your work and you've made such an incredible contribution to the field of metabolic health and type 2 diabetes. So open invite to come back and sit down with me whenever you'd like. Thank you very much, Simon. A pleasure. There you have it, friends. I hope you enjoyed this episode. If you did and want to stay up to date with future episodes, be sure to hit that subscribe button on YouTube and follow on Apple or Spotify. Finally, thank you for showing up and the effort that you're making to take control of your health.

1:27:19I look forward to hanging out with you again in the next episode.